Mechanisms underlying remediation of depression-associated anxiety by chronic N -acetyl cysteine treatment
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ORIGINAL INVESTIGATION
Mechanisms underlying remediation of depression-associated anxiety by chronic N-acetyl cysteine treatment Suwarna Chakraborty 1
&
Sunil Jamuna Tripathi 1
&
T. R. Raju 1
&
B.S. Shankaranarayana Rao 1
Received: 11 March 2020 / Accepted: 11 June 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Rationale Anxiety is one of the most comorbid conditions with major depressive disorder (MDD). Depression-associated anxiety often stems from the dysfunctional hypothalamic-pituitary-adrenal (HPA) axis and its altered regulation by the amygdala. Furthermore, MDD is associated with altered glutamatergic processing leading to anxiety and impaired regulation of the HPA axis. Recent studies have demonstrated that N-acetyl cysteine (NAC), a pleiotropic drug, exerts antidepressant-like effect by modulation of hippocampal functions, periterminal release of glutamate, and/or redox systems. However, the effects of NAC on depression-associated anxiety, HPA axis hyperactivity, and amygdalar dysfunctions are relatively unknown. Objectives Accordingly, we evaluated the effect of NAC on neonatal clomipramine (CLI)-induced adulthood anxiety and accompanying changes in plasma corticosterone levels, amygdalar volumes, neuronal/glial densities, levels of monoamines, and their metabolites in the amygdalar complex. Results We found that chronic treatment with NAC reverses CLI-induced anhedonia and enhanced anxiety. Interestingly, attenuation of CLI-associated anxiety in NAC-treated rats were accompanied by a reversal of adrenal and spleen hypertrophy, and normalization of enhanced plasma corticosterone levels, indicating improved HPA axis functioning. Furthermore, NAC treatment was sufficient to reverse volumetric hypertrophy of basolateral amygdala (BLA), and altered noradrenaline (NA) metabolism in the amygdalar complex. The effects of NAC in the reversal of CLI-induced impairments were similar to that of fluoxetine (FLX). Conclusions We suggest that beneficial effects of NAC on antidepressive- and antianxiety-like behaviors are at least in part mediated via restoration of amygdalar and HPA axis functioning. Our results support the hypothesis that NAC might be evolved as a therapeutic strategy for reversal of amygdalar dysfunction in depression. Keywords N-acetyl cysteine (NAC) . Anxiety . Depression . Hypothalamic-pituitary-adrenal (HPA) axis dysfunctions . Basolateral amygdalar hypertrophy
Abbreviations 5-HIAA 5-Hydroxyindoleacetic acid 5-HT 5-Hydroxytryptamine (serotonin) 5-HTT Serotonin transporter BLA Basolateral nucleus of amygdala CeA Central nucleus of amygdala CLI Clomipramine DA Dopamine DOPAC 3,4-Dihydroxyphenylacetic acid * B.S. Shankaranarayana Rao [email protected]; [email protected] 1
Department of Neurophysiology, National Institute of Mental Health and Neuro Sciences (NIMHANS), Hosur Road, Bengaluru 560 029, India
FLX FSL HPA axis HVA LA LC MDD MHPG NA NAC NSFT PFC PVN SPT VCT
Fluoxetine Flinders sensitive line Hypothalamic-pituitary-adrenal axis Homovanillic
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